TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update

Refractory ascites is a frequent complication of advanced cirrhosis and is associated with hepatorenal syndrome and hepatic hydrothorax. Large volume paracentesis and pleurodesis are regarded as first-line treatments in patients who do not respond adequately to diuretics. These treatments, however, do not prevent recurrence and carry the risk of worsening of the circulatory dysfunction leading to hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt ( TIPS) has been proposed as an alternative to paracentesis. TIPS reduces the rate of ascites recurrence mainly due to the reduction in the filtration pressure. In addition, TIPS results in a positive effect on renal function, including hepatorenal syndrome, demonstrated by a rapid increase in urinary sodium excretion, urinary volume, and improvement in plasma creatinine concentration. Furthermore, plasma renin activity, aldosterone, and noradrenalin concentrations improve gradually after TIPS insertion suggesting a positive effect on systemic underfilling, the factor of hepatorenal syndrome. As demonstrated recently in two meta-analyses including five randomised studies, TIPS also improves survival when compared with paracentesis. However, the evidence is based on relatively few studies with only 305 patients included. The positive effects of the TIPS are opposed by an increased frequency and severity of episodes of hepatic encephalopathy which may be reduced by both patient selection and reduced shunt diameter. Based on the present knowledge the recommended hierarchy of treatments for refractory ascites may be reconsidered upgrading TIPS in suitable candidates

Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report

<p>Abstract</p> <p>Background</p> <p>Portopulmonary hypertension (PPHTN) is a severe complication in liver cirrhosis. PDE5 inhibitors lower pulmonary arterial pressure (PAP) in PPHTN. However, their effect on portal hypertension has not yet been investigated.</p> <p>Case presentation</p> <p>A 55 year old male patient presented with PPHTN and alcoholic liver cirrhosis. 10 mg of Tadalafil, a PDE5 inhibitor with a long half-life, was administered orally under continuous monitoring of pulmonary and portal hemodynamics. For maintenance therapy the patient received Sildenafil 20 mg bid.</p> <p>Tadalafil lowered mean PAP from 45 to 39 mmHg within 60 minutes. Cardiac output (CO) increased from 6.8 to 7.9 l/min. Central venous pressure (CVP) remained stable at 3 mmHg. Systolic and diastolic blood pressure was lowered from 167/89 to 159/86 mmHg. Pulse rate increased from 75 to 87 per min. Wedged hepatic vein pressure (WHVP) decreased from 21 to 18 mm Hg, hepatovenous pressure gradient (HVPG) decreased from 10 to 7 mmHg. Hemodynamic monitoring after 6 months of Sildenafil therapy revealed a sustained lowering of mean PAP. HVPG remained constant at 10 mmHg. Cardiac and pulmonary performance had further improved.</p> <p>Conclusion</p> <p>This case report shows for the first time, that phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension.</p

Smaller-Diameter Covered Transjugular Intrahepatic Portosystemic Shunt Stents Are Associated With Increased Survival

BACKGROUND & AIMS: We studied the effects of diameter of covered, self-expandable, nitinol stents on survival times of patients with a transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We collected data from 185 patients (median age, 55 y; 30% female) who received a covered nitinol stent, from February 2006 through September 2010, using the online multicenter German TIPS registry. TIPS were given to 107 patients for refractory ascites and to 78 patients for variceal bleeding. Patients at risk of hepatic encephalopathy (owing to advanced age, prior episodes) or liver failure (bilirubin level, >3 mg/dL), and bleeding patients receiving variceal embolization at TIPS, received 8-mm stents (n = 53). The remaining patients received 10-mm stents (n = 132). Eighty-one of the 10-mm stents were underdilated using 8-mm dilation balloons. Clinical and biochemical data were collected after TIPS placement at 1 month, 3 months, 6 months, 9 months, 1 year, and thereafter every 3 to 6 months. Groups were compared using propensity score analysis. RESULTS: Patients who received 8-mm stents survived significantly longer (34 +/- 26 mo) than patients who received 10-mm stents (18 +/- 19 mo), regardless of whether they were fully dilated or underdilated. When we compared 10-mm stents with or without underdilation, we found that a significantly higher proportion of patients who received underdilated stents survived for 1 month after TIPS placement (95% vs 84%; P = .03), but not for 3 months (P = .10). In multivariate analysis, 1-year mortality correlated with full dilation of the stent to 10 mm (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5) and with serum creatinine concentration at baseline (HR, 1.5; 95% CI, 1.0-1.7). Five-year mortality was associated with use of the 10-mm stents (HR, 1.8; 95% CI, 1.4-2.7) and baseline concentration of creatinine (HR, 1.3; 95% CI, 1.1-1.6). CONCLUSIONS: A smaller stent (nominal diameter of 8 mm, but not underdilation of a 10-mm stent) is associated with a prolonged survival compared with 10-mm stents, independent of liver-specific prognostic criteria

Structural characterization of soluble E-Syt2

The protein family of membrane-anchored extended synaptotagmin-like proteins (E-Syts) was recently discovered in humans. E-Syt1 to 3 each contain at least one transmembrane domain and three or five C2 domains. To investigate the whole C2 area of murine E-Syt2, highly pure recombinant E-Syt2 (rE-Syt2) covering all three C2 domains was isolated. The structure of rE-Syt2 was studied by small-angle X-ray scattering (SAXS) providing a three-dimensional image of a protein with three C2 domains. Calcium binding of rE-Syt2 triggered structural rearrangements and initiated reversible multimerization of the protein in vitro. Quantitative analysis of the calcium binding revealed an apparent binding constant of 100muM. This is the first structural study of a multi-C2 protein, presumably involved in Ca-dependent signalling events

Probing the existence of non-thermal Terahertz radiation induced changes of the protein solution structure

During the last decades discussions were taking place on the existence of global, non-thermal structural changes in biological macromolecules induced by Terahertz (THz) radiation. Despite numerous studies, a clear experimental proof of this effect for biological particles in solution is still missing. We developed a setup combining THz-irradiation with small angle X-ray scattering (SAXS), which is a sensitive method for detecting the expected structural changes. We investigated in detail protein systems with different shape morphologies (bovine serum albumin, microtubules), which have been proposed to be susceptible to THz-radiation, under variable parameters (THz wavelength, THz power densities up to 6.8 mW/cm$^2$, protein concentrations). None of the studied systems and conditions revealed structural changes detectable by SAXS suggesting that the expected non-thermal THz-induced effects do not lead to alterations of the overall structures, which are revealed by scattering from dissolved macromolecules. This leaves us with the conclusion that, if such effects are present, these are either local or outside of the spectrum and power range covered by the present study

Structural basis for autoinhibition of ESCRT-III CHMP3

Endosomal sorting complexes required for transport (ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III) are selectively recruited to cellular membranes to exert their function in diverse processes, such as multivesicular body biogenesis, enveloped virus budding, and cytokinesis. ESCRT-III is composed of members of the charged multivesicular body protein (CHMP) family--cytosolic proteins that are targeted to membranes via yet unknown signals. Membrane targeting is thought to result in a membrane-associated protein network that presumably acts at a late budding step. Here we provide structural evidence based on small-angle X-ray scattering data that ESCRT-III CHMP3 can adopt two conformations in solution: a closed globular form that most likely represents the cytosolic conformation and an open extended conformation that might represent the activated form of CHMP3. Both the closed and open conformations of CHMP3 interact with AMSH with high affinity. Although the C-terminal region of CHMP3 is required for AMSH interaction, a peptide thereof reveals only weak binding to AMSH, suggesting that other regions of CHMP3 contribute to the high-affinity interaction. Thus, AMSH, including its MIT (microtubule interacting and transport) domain, interacts with ESCRT-III CHMP3 differently from reported Vps4 MIT domain-CHMP protein interactions